To learn more about the site and mode of action of propofol, the authors anesthetized rats with urethane, and implanted a stimulating electrode in the perforant pathway and a recording electrode in the hippocampal dentate gyrus to measure evoked field responses. Catheters were placed in the jugular vein and carotid artery to measure blood pressure, take blood samples for measurement of blood gases, and inject drugs. Rat lungs were ventilated, and increasing doses of propofol or its 10% fat emulsion vehicle were administered. Over a dose range of 2.5-40 mg/kg, propofol had little effect on the field excitatory postsynaptic potential (EPSP) or the field population spike (PS), suggesting no important actions on perforant pathway fibers or intrinsic granule cell excitability. With the use of various paired-pulse stimulation paradigms, it was demonstrated that propofol administration led to a dramatic decrease in granule cell excitability over interpulse intervals of 10-100 ms. The magnitude of this effect clearly was related to dose, and the effect was reversible with discontinuance of drug. The vehicle had marginal effects on granule cell excitability. These were significantly less than those produced by propofol. Transient reductions in blood pressure followed by transient increases to above baseline were observed after administration of propofol at most doses. Increased heart rates accompanied the slight increase in blood pressure. Except at the largest dose of propofol tested, cardiovascular measures had returned to near control levels by 8 min, when the evoked potentials were evaluated. Arterial blood gases showed little change throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)